Renal Cell (RCC) and Bladder Carcinoma (TCC) · Renal Cell (RCC) and Bladder Carcinoma (TCC) Prof....

Renal Cell (RCC) andBladder Carcinoma (TCC)

Prof. Dr. med. Viktor Grünwald

Klinik für Hämatologie, Hämostaseologie, Onkologie und

Stammzelltransplantation

DisclosuresCompensated lectures:

BMS, Ipsen, Eisai, Novartis, Pfizer, Roche

Advisory: Astac Zeneca, Bayer, BMS, Cerulean, Ipsen, Eisai, Novartis, Pfizer, Roche

Research grants: Astra Zeneca, BMS, MSD, Pfizer, Novartis

Stock shareholder :none

Checkpoint Blockade in GU Cancer

Carinoma Status outcome

Renal cell Phase III positive

Urothelial Phase III positive

Prostate Phase III negative

Germ cell Basket study -

Penile Basket study -

PD-L1 – a negative predictor

Gevensleben et al. (2016). CCR, 22(8), 1969–1977. Thompson et al. Proc Natl Acad Sci USA 2004;101:17174–9. Cierna et al. (2016). Annals of Oncology, 27(2), 300–305.

PCA RCC GCT

Don‘t be too advanced for the field: Sipuleucel-T in PCA

Kantoff et al. (2010). NEJM, 363(5), 411–422. Fong et al. (2014). JNCI Journal of the National Cancer Institute, 106(11)

HR 0,78 (0,61-0,98)P=0,03

PCA: Ipilimumab vs. Placebo

Kantoff et al. (2010). NEJM, 363(5), 411–422.

Mutational load of GU cancers varies

MS Lawrence et al. Nature 2013

...so does immune cell infiltration

Mandal, R., Senbabaoglu, Y., Desrichard, A., Havel, J. J., Dalin, M. G., Riaz, N., et al. (2016). JCI Insight, 1(17), e89829. http://doi.org/10.1172/jci.insight.89829

Immunotherapy –not a one-size-fits-all approach

CD8T cellwith

granzyme B

CD8

T cellwith PD-L1

expression

Immunogenic tumor

microenvironment

Nonimmunogenic tumormicroenvironment

Combination therapies

with agents that create

immunogenic tumor

microenvironment and

immune checkpoint therapy

Durable clinical benef tImmune checkpoint ther apy

and durable clinical benef t

CD8T cell

with CD45ROexpression

CD8T cell

CD4T cell

Tumorcell

with PD-L1expression

BA

Sharma & Allison. The future of immune checkpoint therapy. (2015). The future of immune checkpoint therapy. Cancer

Immunology Immunotherapy, 1–7.

hot tumor

single agent

cold tumor

combination

OS-benefit for Nivolumab in 2nd line

Motzer RJ et al. N Engl J Med, 2015; 373: 1803–13.

Plimack et al. KCS 2016

2-year-Follow-up

...but, only minor improvement in PFS

Motzer et al. (2015). NEJM, 150925150201006–11. http://doi.org/10.1056/NEJMoa1510665.

44% received treatment beyond progression for nivolumab, and 46% for everolimus

Geonomic profile differs by line in mRCC (ctDNA analysis)

Pal et al. (2017). European Urology. http://doi.org/10.1016/j.eururo.2017.03.046

What about combinations in RCC?

Immunogenic cell death – the goalof combinations with RTX or CTX

Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L., & Kroemer, G. (2017). Nature Reviews. Immunology, 17(2), 97–111. http://doi.org/10.1038/nri.2016.107

Immunotherapy – a matter ofcombinations?

Salama, A. K. S., & Moschos, S. J. (2016). Annals of Oncology, mdw534. http://doi.org/10.1093/annonc/mdw534

death-ligand 1; VEGF, vascular endothelial growth factor.

Res. 2008; McDerm

ott, J ClinOncol. 2016; W

allin. Nat Comm

un. 2016.

g the Balance Toward Anti-Cancer Imm

unity

ombined VEGF/PD-L1 Blockade

Atezolizumab

Atezolizumab

Bevacizumab

Sunitinib

Anti-Cancer Imm

unity

McDerm

ott D, et al. IMm

otion150 bioma

Bevacizumab/Atezolizumab –improved T-cell-migration

Wallin et al. (2016). Nature Communications, 7, 12624. http://doi.org/10.1038/ncomms12624

IC3+ RCC Patient: PR with atezolizumab

Herbst et al. (2014). Nature, 515(7528), 563–567. http://doi.org/10.1038/nature14011

ATEZO-BEV: PFS (ITT)

Atezo, atezolizumab; Bev, bevacizumab.a P values are for descriptive purposes only and not adjusted for multiple comparisons.

Stratified HR

(95% CI)P Valuea

Atezo + bev vs

sunitinib

1.00

(0.69, 1.45)0.982

Atezo vs

sunitinib

1.19

(0.82, 1.71)0.358

Atezolizumab + bevacizumab

Atezolizumab

Sunitinib

Atezo + bev: 11.7 mo (8.4, 17.3)

Atezo:6.1 mo

(5.4, 13.6)Sunitinib:8.4 mo (7.0, 14.0)

McDermott et al. ASCO GU 2017: 431

Dual Checkpoint Blockade – a future was of treatment?

Hammers et al. ASCO 2015 #4516. Hammers et al. ESMO 2016: 1062P

IPI3 +

NIVO1

IPI1 +

NIVO3

ORR 40% 40%

PD 17% 17%

PFS 6,6 Mo. 9,1 Mo.

Efficacy of dual checkpointinhibition in mRCC

Hammers et al. ESMO 2016: 1962P

VEGF inhibition triggers PD-L1 expression

Liu et al. Cancer Immunol Res; 3(9); 1–12.

100

Cha

ng

e in b

aselin

e (

%)

Time since first dose (weeks)

80

60

40

20

-20

-40

-60

-80

-100

120 36 48 60 72 84

1st occurrence of new lesion

24

0

120 36 42 48 54 6024 6630186 120 36 48 60 9624 72 84

SU+NIVO pretreated(n=13)

SU+NIVO Rx-naive (n=15)

PAZ+NIVO pretreated(n=19)

Amin et al. ASCO 21014: #5010

ORR: 52% (n=17/33)

PFS: 49 wks.

ORR: 45% (n=9/20)

PFS: 31 wks

Do we have proper marker forpatient selection?

Checkmate-025:

PD-L1 is not predictive for nivolumab

Motzer RJ et al. N Engl J Med, 2015; 373: 1803–13

Res.2012; Herbst, Nature2014; Powles, SITC

2015; Fehrenbacher, Lancet2016.

iptome M

ap of Angiogenesis and Imm

une-Associatedn RCC Tum

ors

mm

une,

entation

Myeloid

mm

ation

McDerm

ott D, et al. IMm

otion150 bioma

genesis

PD-L1 IHC

(e.g., CD34, KDR, VEGFA)

(e.g. CD8A, IFNG, PSMB8)

(e.g. IL6, PTGS2, IL8)

signature: VEGFA, KDR, ESM1, PECAM

1, ANGPTL4, CD34.

� median expression, Angiogenesis Low: < m

edian expression.

bDem

onstrated Improved PFS in Angiogenesis

HighSogenesis

LowSubset

Sunitinib

HR95%

CI

isw)

0.31(0.18, 0.55)

Atezolizumab + Bevacizum

ab

HR95%

CI

Angiogenesis

(High vs Low)0.90

(0.54, 1.51)

AtezolizuH

Angiogenesis

(High vs Low)

0.7

High (n = 44)

Low (n = 45)

Sunitinib

High (n = 45)

Low (n = 43)

Atezolizumab + Bevacizum

abAtezolizu

McDerm

ott D, et al. IMm

otion150 bioma

ature: CD8A, EOMES, PRF1, IFNG, CD274.

edian expression, T-effector Low: < median expression.

umab and Bevacizum

ab Demonstrated Im

proved PFStinib in the T-Effector HighSubset

Atezo+ be

Atezo(n =

Sunitinib (n

T-effector High

Atezo+ bev(n =

46)

Atezo(n = 40)

Sunitinib (n = 46)

T-effector Low

HR (95% CI)

T-effector LowT-effector High

Atezo+ bev

vs sunitinib1.41 (0.84, 2.36)

0.55(0.32, 0.95)

Atezovs sunitinib

1.33(0.76,2.33)

0.85 (0.50, 1.43)

McDerm

ott D, et al. IMm

otion150 bioma

Res.2012; Herbst, Nature2014; Powles, SITC

2015; Fehrenbacher, Lancet2016.

iptome M

ap of Angiogenesis and Imm

une-Associatedn RCC Tum

ors

PD-L1 IHC

PD-L1 IHC

IC0IC1

IC2IC3

-32

-2-1

10

T-effector HighSubpopulation

T-effector High

Myeloid Inflam

mation

Low

T-effector Hi

Myeloid Inflam

ma

McDerm

ott D, et al. IMm

otion150 bioma

nature: CD8A, EOMES, PRF1, IFNG, CD274.

ession, Low: < median expression.

n of Bevacizumab to Atezolizum

ab is Associated With

ed Benefit in T-effector High/Myeloid Inflam

mation

HighSu

T-effector HighMyeloid

Hig

Atez

Atez

Suni

T-effector HighMyeloid

Low

Atezo+ bev(n =

23)

Atezo(n = 23)

Sunitinib (n = 19)

McDerm

ott D, et al. IMm

otion150 biomar

on

ssed ORR.

orrelates With PFS in Gene Expression Subgro

h 44

Low n = 41

High n = 42

Lown = 4

% %

10%16%

33%

17%

High n = 44

Low n = 42

High n = 41

Low n = 44

High n = 45

Low n = 40

High n = 43

Low n = 42

Angiogenesis SignatureT-effector Signature

nitinibSunitinib

AtezoAtezo

Atezo+ bev

Atezo+ b

9%12%

12%14%

12%

29%

20%5%11%

5%

20%

10%5%

2%

24%25%

McDerm

ott D, et al. IMm

otion150 bioma

What about response?

Depth of remission isprognostic in RCC (TKI-era)

Grünwald V et al. ESMO 2013, Amsterdam, #2702; EUR UROL 2015

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 10 20 30 40 50 60

Su

rviv

al

Pro

ba

bil

ity

Time (Months)

Median OS (m)

–100% to –60% (n=283) 54.53

–60% to –30% (n=547) 26.38

–30% to 0% (n=1155) 16.56

0% to +20% (n=390) 10.36

≥20% (n=156) 7.33

No post-baseline scan (n=218) 1.97

CM025: OS according to bestresponse at 4 mo.

Motzer et al. ASCO 2016

QoL-responders gain OS-benefit

HR-QoL responders (2 pts..):

• NIVO (55%) > EVE (37%)

• Faster with NIVO (4.7 mo. vs.

NR)

Cella et al. ASCO 2016 #4549

Conclusion RCC

• GU-cancers are immunogenic

• Nivolumab has improved 2nd line treatment in RCC

• Depth of remission is prognostic with targeted therapies

in RCC

• Combinations may improve efficacy

• Gene signatures may guide future choice of therapy

Urothelial Carcinoma

Systemic therapy in TCC

1st Linie- Cisplatin/Gemcitabine

- (DD-MVAC)

2nd Linie- Vinflunine

- Taxane- (Ifosfamide)

1st Linie: frail- Carboplatin/Gemcitabine

- Gemcitabine- Taxane

Bellmunt et al. ESMO Guidelines Working Group. (2014, September). Annals of Oncology. http://doi.org/10.1093/annonc/mdu223

VICTOR: UK-real worldretrospective Data for vinflunine

Hussain et al. (2017), International Journal of Oncology, 50(3), 768–772. http://doi.org/10.3892/ijo.2017.3847

Chemotherapy in mTCC

Bellmunt et al. (2012). JCO, 30(10), 1107–1113. Bellmunt et al. (2009). JCO, 27(27), 4454–4461. http://doi.org/10.1200/JCO.2008.20.5534

ORR: 44%OS: 12,7 Mo.PFS: 7,6 Mo.

1st line 2nd line

ORR: 9%PFS: 3 Mo.

Long-term survival with CTX

PCG1

n=312GC1

n=314GC2

n=203MVAC2

n=202MVAC3

n=129DD-MVAC3

n=134

PFS (mo.) 7.6 8.3 7.7 8.3 8.2 9.1

2y-PFS rate - - 14% 18% 12 25

5y-PFS rate - - 10% 11% - -

OS (mo.) 15.8 12.7 14 15.2 14.1 15.5

2y-OS rate - - 25% 31% 25 35

5y-OS rate 17%* 16%* 13% 15% 10%§ 14%§

1Bellmunt et al. (2012). JCO, 30(10), 1107-11132van der Maase et al. (2005). JCO, 23(21), 4602–4608.3Sternberg et al. (2001). JCO, 19(10), 2638–2646.

Inflammatory TCC –association with better OS

Bellmunt et al. (2015). Annals of Oncology, mdv009. doi:10.1093/annonc/mdv009

TIMC: tumor infiltrating monocytic cells

12 mo.

23 mo.

PD-L1+ TIMC analysed

Checkpoint inhibitors in mTCC

Massard et al. (2016). JCO, 34(26), JCO679761–3125. Apolo et al. (2017). JCO, 2016.71.679. Balar et al. ESMO 2016. Sharma et al. ASCO 2016: 4501.

Durvalumab Avelumab

-100

-80

-60

-40

-20

0

20

40

60

80

100

C h a

n g e F r

o m B

a s e l i n

e , %

20% increase

30% decrease

52% experienced a decrease in target lesions

PembrolizumabNivolumab

PD-L1

PD-1

Activity of PD-(L)1i in mTCC

ATEZO1 ATEZO2 NIVO3 NIVO4 PEMBRO5 AVELU6 DURVA7

N 119 310 78 270 100 129 61

Line CDDP unfit ≥2. ≥2. ≥2. CDDP unfit ≥2. or

CDDP unfit

≥2. or

CDDP unfit

CR (%) 7 7 6 2 6 3 -

PR (%) 17 16 18 17 18 14 31

OS (mo.)

14.8 7.9 9.7 8.7 - - -

FDA license ✓ ✓ ✓ ✓ ✓ ✓ ✓

1Balar et al. ASCO 2016 #4500. 2Dreicer et al.ASCO 2016 #4515. 3Sharma et al. ASCO 2016 #4501. 4Galsky et

al. ESMO 2016 LBA31. 5Balar et al. ESMO 2016 LBA32. 6Patel ESMO 2016: 2534. Massard et al. (2016). JCO,

34(26), JCO679761–3125.

1st Linie TCC: Atezolizumab(IMvigor210): CDDP-unfit

Bellmunt et al. ESMO 2016, 782PD

57%

1st line CDDP-unfit: chemotherapy

De Santis et al. (2012). JCO, 30(2), 191–199. De Santis et al. (2015). Annals of Oncology, mdv609.

approx. 38%

phase II 2011-2012: Vinflunine-doublet (GEM or CARBO)ORR: 44 vs. 29%PFS: 5.9 vs. 6.1 mo.OS: 12.8 vs. 14.0 mo. (P=0.86)

2001-2008OS:8.1 vs. 9.3 mo.

IMvigor210: platinum-failure

Loriot et al. ESMO 2016: 783P

IC0/1 n=210

IC2/3n=100

Alle Pts.N=310

OS; Mo.

(95% CI)

6,7

(5,4-8,0)

11,9

(9,0-NE)

7,9

(6,7-9,3)

12-Mo. OS 31% 50% 37%

Atezolizumab

approx.. 38%

All treated patients

No. at RiskAll treated patients

PD-L1 <1%

PD-L1 ≥1%

PD-L1 ≥1%

Median OS, Months (95% CI)a

All treated 8.74 (6.05–NR)

PD-L1 <1% 5.95 (4.30–8.08)

PD-L1 ≥1% 11.30 (8.74–NR)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15

Overa

ll S

urv

ival (P

rob

ab

ilit

y)

Months

PD-L1 <1%

aSimilar results were seen using the 5% PD-L1 tumor expression cutoff; NR, not reached

265 198 148 63 5 0143 101 69 26 2 0122 97 79 37 3 0

Galsky et al. ESMO 2016: LBA31

approx.. 40%

Nivolumab (Platinum-failure)

OS in 2nd line with chemotherapy

Bellmunt et al. (2009). JCO, 27(27), 4454–4461. http://doi.org/10.1200/JCO.2008.20.5534Bellmunt et al. (2013). Annals of Oncology, 24(6), 1466–1472. http://doi.org/10.1093/annonc/mdt007

27% Vinflunine

22% BSC

Atezolizumab: similar outcome by line of Rx

Perez-Garcia et al. ASCO GU 2017: 323

2nd line TCC KN45 (OS)

Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683

CTX Dealers choice:DocetaxelPaclitaxelVinflunine

PFS: Pembrolizumab vs. CTX

Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683

KN45: adverse events

Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683

KN-45: better HR-QoL with PD-1i

Bellmunt et al. ASCO GU 2017: 282

DOR: longer with pembrolizumab

Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683

What about enrichment?

Durvalumab (mixed cohort)

Powles et al. ASCO GU 2017: 286

Previous therapy: 91%

ORR: 20%PFS: 2.2 mo.OS: 14.1 mo.

Durvalumab in mTCC

Massard et al. (2016). JCO, 34(26), JCO679761–3125. http://doi.org/10.1200/JCO.2016.67.9761

Avelumab in mTCC (mixed cohort)

Apolo et al. (2017). JCO, 2016.71.679. http://doi.org/10.1200/JCO.2016.71.6795

1st line chemotherapy: 1-year-OS rate

approx.60%

van der Maase et al. (2005). JCO, 23(21), 4602–4608.

Treatment effect or independentprognostic factor?

Rosenberg et al. Lancet 2016

Treatment failure occurs despiteenrichment for IC2/3+ TCC

Rosenberg et al. Lancet 2016

Response to atezolizumab shown in IC2/3+ patients according to RECIST defined responses

50%

Are we missing something?

Risks of immunotherapy: hyperprogression

Champiat et al. (2016). CCR.1741.2016. http://doi.org/10.1158/1078-0432.CCR-16-1741

Conclusion TCC

• Chemotherapy-efficacy is limited

• PD-(L)1 inhibitors are active irrespective of prior therapy

• Petter outcome in PD-L1+ TCC

• Phase III data indicate survival benefit (pembrolizumab)

• But, atezolizumab without improvement...